Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Institute of Molecular Biology and Pathology, Department of Biology and Biotechnology, Sapienza University of Rome, 00185 Rome, Italy.
Mol Biol Cell. 2018 Jul 1;29(13):1611-1627. doi: 10.1091/mbc.E18-02-0088. Epub 2018 May 9.
A primary cilium is found on most mammalian cells, where it acts as a cellular antenna for the reception of both mechanical and chemical signals. A variety of diseases are associated with defective ciliogenesis, reflecting the ubiquity of the function of cilia and the number of proteins required for their assembly. Proper cilia length is necessary for cilia signaling and is regulated through a poorly understood balance of assembly and disassembly rates. FHDC1 is a unique member of the formin family of cytoskeletal regulatory proteins. Overexpression of FHDC1 induces F-actin accumulation and microtubule stabilization and acetylation. We find that overexpression of FHDC1 also has profound effects on ciliogenesis; in most cells FHDC1 overexpression blocks cilia assembly, but the cilia that are present are immensely elongated. FHDC1-induced cilia growth requires the FHDC1 FH2 and microtubule-binding domain and results from F-actin-dependent inhibition of cilia disassembly. FHDC1 depletion, or treatment with a pan-formin inhibitor, inhibits cilia assembly and induces cilia resorption. Endogenous FHDC1 protein localizes to cytoplasmic microtubules converging on the base of the cilia, and we identify the subdistal appendage protein Cep170 as an FHDC1 interacting protein. Our results suggest that FHDC1 plays a role in coordinating cytoskeletal dynamics during normal cilia assembly.
大多数哺乳动物细胞都有一个初级纤毛，它作为细胞的天线，用于接收机械和化学信号。许多疾病都与纤毛生成缺陷有关，这反映了纤毛功能的普遍性和组装所需的大量蛋白质。适当的纤毛长度对于纤毛信号传递是必要的，并且通过组装和拆卸速率的不平衡来调节。FHDC1 是细胞骨架调节蛋白formin 家族的独特成员。FHDC1 的过表达诱导 F-肌动蛋白的积累和微管的稳定和乙酰化。我们发现 FHDC1 的过表达对纤毛发生也有深远的影响；在大多数细胞中，FHDC1 的过表达阻止纤毛组装，但存在的纤毛极度延长。FHDC1 诱导的纤毛生长需要 FHDC1 FH2 和微管结合结构域，并且源自 F-肌动蛋白依赖性抑制纤毛解体。FHDC1 耗竭或使用泛formin 抑制剂处理会抑制纤毛组装并诱导纤毛吸收。内源性 FHDC1 蛋白定位于细胞质微管，这些微管汇聚在纤毛的基部，我们鉴定出亚远端附属蛋白 Cep170 是 FHDC1 的相互作用蛋白。我们的结果表明，FHDC1 在正常纤毛组装过程中协调细胞骨架动力学中发挥作用。
